Lassa fever (LF), a severe hemorrhagic illness, is one of the most threatening infectious diseases known because of its unique status as both an immediate public health crisis and a bio-safety level 4 (BL-4) potential bioterror hazard. Endemic in large parts of West Africa, LF is estimated to hospitalize tens of thousands of individuals and cause several thousand deaths each year, with a case fatality rate in hospitalized patients that can reach 50% or more. Antibody-based surveys suggest that infection with the LF-causing agent, Lassa virus (LASV), is far more widespread than previously thought, with over 20% of Nigerians and Sierra Leoneans showing evidence of exposure. It is not known why many West Africans infected with LASV do not exhibit disease symptoms while others go on to suffer encephalitis, deafness and death, but recent genomic studies offer a hypothesis. A genome-wide survey of human genetic variation identified two genes biologically linked to LF infection among the strongest signals of recent human adaptation in West Africans. Further analysis of the LASV genome itself indicates that the virus has been circulating in West Africa for over a millennium. These findings-coupled with the high rates of disease, observed disease resistance, significant mortality and disability in affected individuals, and the widespread exposure to the rodent reservoir for the virus-suggest that LF is an ancient selective force, driving the emergence of genetic variants that confer resistance. LASV's unique status among BL-4 agents as a widespread, long-standing selective force is reflected in the serious global health risk it poses, but also provides a tremendous opportunity to study LF and the genetic mechanisms of resistance to it. Along with our partners in the US and Africa, we have built thriving clinical and research centers in Nigeria and Sierra Leone, and implemented diagnostics, training and infrastructure there to ensure safe, high-quality sample collection from patients hospitalized with LF. We have performed a preliminary genome scan and found several promising candidate adaptive and immune genetic variants associated with LF resistance. We have further developed a number of high-throughput technological approaches to rapidly validate and characterize these variants functionally. Based on our previous success in this area, we propose to pursue genetic determinants of resistance to LF through a larger patient collection, deeper diagnostic characterization, more extensive genetic studies, and functional characterization of candidate variants. Through our study, we hope to lay a foundation for the development of vaccines and diagnostics while also providing a path forward for further research into LASV and other BL-4 agents.